Journal of Inclusion Phenomena and Molecular Recognition in Chemistry 25: 327338, 1996. 327 @ 1996 Kluwer Academic Publishers. Printed in the Netherlands. Interactions Between Naproxen and Maltoheptaose, the Non-Cyclic Analog of/3-Cyclodextrin G. R BETTINETTII, * R MURA 2, F. MELANI 2, M. RILLOSI 1 and F. GIORDANO 3 I Dipartimento di Chimica Farmaceutica, Universitci di Pavia, Viale Taramelli 12, 1-27100 PV, Italy. 2Dipartimento di Scienze Farrnaceutiche, Universitd di Firenze, Via G. Capponi 9, 1-50121 FI, Italy. 3 Dipartimento Farmaceutico, Universitgt di Parma, Viale delle Scienze, 1-43100 PR, Italy. (Received: 15 December 1995; in final form: 19 April 1996) Abstract. The crystallinity of naproxen in solid combinations with amorphous maltoheptaose, the non-cyclic analog of/3-cyclodextrin, was assessed using differential scanning calorimetry supported by X-ray powder diffractometry. Cogrinding induceda decreasein drug crystallinityto an extent which depended on the grinding time, and was most pronounced for the combination of equimolecular composition. Thermal analysis showed that the mechanism behind the conversion of crystalline naproxeninto the amorphousstate by cogrindingwith maltoheptaosedifferedfrom that with randomly substituted, amorphous/3-cyclodextrins. Interactions of naproxen with maltoheptaose in aqueous solutionwere studied by means of fluorescencespectroscopy, phase-solubility analysis,and computer- aided molecular modelling. Maltoheptaose can wrap up naproxen, taking on a cyclic conformation and forming a 'pseudo' inclusion complex (apparent binding constant KI: 1 = 1.0 x 10 3 (4-20%) L mol-1 at 25 °C) which is about as stable as the true inclusion complex with/3-cyclodextrin in the lowest temperature range (0-100 K). A better complexing ability for naproxen in terms of binding constant values, however, was displayed by both native and derivatized/3-cyclodextrins, the 'hosts' with covalently-boundcyclic structures. Key words: Maltoheptaose, naproxen, naproxen-maltoheptaose blends, grinding, crystallinity,com- plexation, thermal analysis, X-ray diffractometry, molecular modelling. 1. Introduction The shift from the poorly water-soluble (<0.029/gwater at room temperature) nat- ural /3-cyclodextrin to the more soluble (>0.59/gwater) chemically-modified/3- cyclodextrins improves the pharmaceutical usefulness of these host substances as solubilising, dissolution rate-enhancing, and complexing agents for the naproxen guest molecule, a potent non-steroidal antiinflammatory drug with very poor water solubility [1-4]. Moreover, random substitution of/3-cyclodextrin results in the amorphous state, which in turn may be conferred on crystalline naproxen in solid combinations [1-4]. Since maltoheptaose, the noncyclic analog of/3-cyclodextrin, or 'open'/3-cyclodextrin, is also amorphous, a study of the naproxen-maltoheptaose system in the solid state and in aqueous solution was undertaken, using differential scanning calorimetry supported by X-ray powder diffractometry, and fluorescence * Author for correspondence.